The Compromised Fanconi Anemia Pathway in Prelamin A‐Expressing Cells Contributes to Replication Stress‐Induced Genomic Instability
Abstract: Genomic instability is not only a hallmark of senescent cells but also a key factor driving cellular senescence, and replication stress is the main source of genomic instability. Defective prelamin A processing caused by lamin A/C (LMNA) or zinc metallopeptidase STE24 (ZMPSTE24) gene mutations results in premature aging. Although previous studies have shown that dysregulated lamin A interferes with DNA replication and causes replication stress, the relationship between lamin A dysfunction and replication stress remains largely unknown. Here, an increase in baseline replication stress and genomic instability is found in prelamin A‐expressing cells. Moreover, prelamin A confers hypersensitivity of cells to exogenous replication stress, resulting in decreased cell survival and exacerbated genomic instability. These effects occur because prelamin A promotes MRE11‐mediated resection of stalled replication forks. Fanconi anemia (FA) proteins, which play important roles in replication fork maintenance, are downregulated by prelamin A in a retinoblastoma (RB)/E2F‐dependent manner. Additionally, prelamin A inhibits the activation of the FA pathway upon replication stress. More importantly, FA pathway downregulation is an upstream event of p53‐p21 axis activation during the induction of prelamin A expression. Overall, these findings highlight the critical role of FA pathway dysfunction in driving replication stress‐induced genomic instability and cellular senescence in prelamin A‐expressing cells.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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The Compromised Fanconi Anemia Pathway in Prelamin A‐Expressing Cells Contributes to Replication Stress‐Induced Genomic Instability ; day:18 ; month:06 ; year:2024 ; extent:15
Advanced science ; (18.06.2024) (gesamt 15)
- Urheber
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Nie, Pengqing
Zhang, Cheng
Wu, Fengyi
Chen, Shi
Wang, Lianrong
- DOI
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10.1002/advs.202307751
- URN
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urn:nbn:de:101:1-2406191441224.049264717327
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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14.08.2025, 10:50 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Nie, Pengqing
- Zhang, Cheng
- Wu, Fengyi
- Chen, Shi
- Wang, Lianrong
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